G-acyloxy-x-methylhexyne-z-diol-i



June 5, 1951 M. 6ACYLOXY-4-METHYLHEXYNE-:2-DIOL-1 4 S NEWMAN AND METHOD FOR PRODUCING THE SAME Filed May 10, 1947 4 Sheets-Sheet l l-HYDROXY-S-BUTANONE PYRIDINE TRIMETHYLACE'TYL CHLORlDE PHENYL LITHIUM PROPARGYL ALcoHol.

(m swan) ETH ER ADDED ET HER EXTRAfllON VAOUU M DB1 ILLATION I'TRIMET HYLAC ETOXY 3- DUTANONE AMMONWM CHLORIDE SOLUTION DISTILLATION 6-TRlMETHYLACETOXY-4 METHYLHEXYNE-t-DIOL-LB Fig.1.

- uvmvrm B MELVIN SPENCER NEWMAN ATTORNEY June 5, 1951 M. s. NEWMAN 2,555,598

6-ACYLOXY-4METHYLHEXYNE-2-DIOL-l,4 AND METHOD FOR PRODUCING THE SAME Filed May 10, 1947 V 4 Sheets-Sheet 2.

ETHER 'I' I'HYDROXY-B-BUTANONE PYRIDINE +BENZQYL CHLORIDE WITH STIRRING I WATER 5DDED| TI-IER EXTRACTION VACUUM DISTILLATION h-acnzoxv -3-auTAnon:| Y PHENYLMAGNESIUM ammo: PROPARGYL ALCOHOL m amzsu:

ADD nvnaommme l unomLomoz kwnaowzen wrrn ACETIC Acnfl SUDIUM HYDROXIDE [usuwmuzco wrra soonm BICARBONATII I-BENZOXY-3-BUTANONE E HER EXTRACTION OXI ME I VACU M DISTILLATION RESIDUE DISTILLED PORTION OF STARTING MATERIAL BIPHENYI. 4

HEATED T0 Rcrwx POURID- IN WAT ER lssmwnou AND cn'vsTALuzA'noul I DI -P- NITRODENZOATE OF 6' an: OXY-4- METHYLHEXYN I:

-zom. m

IN VEN TOR.

MELVIN SPENCER NEWMAN ATTORN Y June 5, 1951 M. s. NEWMAN 2,555,598

6-ACYLOXY-4-METHYLHEXYNE-2-DIOL-l 4 AND METHOD FOR PRODUCING THE SAME Filed May 10, 1947 4 Sheets-Sheet 3 CH a i CCH -CH:-O-C-C\- CH u Fig.5.

CH CH 3 HOCHrC C-C ..\-I -CH -C)--C-C--C2H OH CH;

Fig.4.

IN VEN TOR.

MELVIN SPENCER NEWMAN BY ATTOR EY June 5, 1951 M. s. NEWMAN 2,555,598

' 6-ACYLOXY-4-METHYLHEXYNE-2-DIOL-l ,4

AND METHOD FOR PRODUCING THE SAME Filed May 10, 1947 4 Sheets-Sheet 4 i a o I C O 9 e c cHz'cH -o-c C ll NOH Fig.8.

cu=cu CH -0H W5 o u-c ocoocu -ca ca-q-cu -curo-c-c cu Fig.7.

INVENTOR. MELVIN SPENCER NEWMAN ATTORN Y Patented June 5, 1951 6-ACYLOXY-4-METHYLHEXYNE-2-DIOL-1,4 AND METHOD FOR PRODUCING THE SAME Melvin S. Newman, Columbus, Ohio, assignor to Ohio State University. Research Foundation, Columbus, Ohio, a corporation of Ohio Application May 10, 1947, Serial No. 747,175

11 Claims. (01. 260-476) This invention relates to new compounds or compositions of matter useful as intermediates in the synthetic production of vitamin A or its esters and to processes for synthesizing such new compounds. It is illustrated by processes of forming acyloxy methylhexyne diols having the formula where R is a member of the class consisting of alkyl, aryl, aralkyl and cycloalkyl. Prior hereto there has been no recognized method of preparing fi-acyloxyl-methylhexyne-2-diols-1,4. Nor have these materials been previously synthesized nor isolated.

One of the objects of my invention is the production of new and useful compositions of matter useful as intermediate chemical compounds in the synthesizing of vitamin A or its esters, of similar compounds and of other chemicals.

Another object of my invention is the provision of new methods of synthesizing such various intermediates and other chemicals.

A further object of my invention is the synthesizing of acyloxy butanones and new methylhexyne-diols and the provision of methods for synthesizing such compounds.

Features of the processes described herein in illustration of my invention include the synthesis of such products by reaction of a hydroxybutanone and pyridine with acyl chloride and the subsequent reaction of the product thereof with a propargyl metal derivative formed by mixing with propargyl alcohol any suitable organo metallic reagent such as, for example, phenyllithium, phenylmagnesium bromide, and butylmagnesium chloride or any other reagent known in the prior art.

Other features of my invention include the synthesis of 6-benzoxy-4-methylhexyne-2-diol- 1,4; 6 trimethylacetoxy 4 methylhexyne 2 diol1,4; l-benzoxy 3 butanone; and 1 tri methylacetoxy-3-butanone.

Further features include the preparation of new compounds by which the methylhexynediols thus formed may be identified.

Further objects and features of the present invention will be apparent from the following description, reference being had to the accompanying drawings wherein preferred forms of embodiments of the invention are clearly shown.

In the drawings:

Fig. 1 illustrates a method of synthesizing one 2 of the substances selected in illustration of my invention, the substances referred to and methods shown constituting some of the preferred embodiments of the invention;

Fig. 2 illustrates a method of synthesizing another of the substances selected in illustration of my invention, the substances referred to and the methods shown constituting others of the preferred embodiments of the invention;

Fig. 3 shows the structural formula of a trimethylacetoxy methylheXyne-diol which may be synthesized by my process;

Fig. 4 shows the structural formula of a benzoxy methylhexyne-diol which may be synthesized by my process;

Fig. 5 shows the structural formula of a trimethylacetoxy butanone which may be synthesized by my process;

Fig. 6 shows the structural formula of a benzoxy-butanone which may be synthesized by my process;

Fig. 7 shows the structural formula of a derivative of the compound shown in Fig. 4, which I used in identifying the benzoxy methylhexynediol; and

Fig. 8 shows the structural formula of a derivative of the compound shown in Fig. 6, which I used in identifying the benzoxy butanone.

In general, one of the processes of my invention. comprises the reaction of 1-hydroxy-3- butanone with an acyl halide in the presence of an acid-binding agent; isolation of the acyloXy-' 3-butanone reaction thereof with a metal derivative of propargyl alcohol; hydrolysis of the organo metallic complex to give the fi acyloxy-e-methyb hexyne-2-diol-L4 which may then be isolated from the reaction mixture and further purified. Any acyl halide can be used within the scope of the invention. For purposes of illustration, trimethylacetylchloride and benzoyl chloride have been used. For an acid-binding agent, any tertiary amine or an aqueous alkali according to the S-chotten-Baumann method may be used. By a metal derivative of a propargyl alcohol, I mean a compound in which a metal is attached directly to the carbon having a triple bond. Among the metals which may be used are the alkali metals such as lithium, potassium and sodium; alkaline earth metals such as calcium or barium; and other metals such as magnesium.

For the preparation of the reagent it is better to react propargyl alcohol with a Grignard reagent or a metal alkyl reagent rather than reacting the propargyl alcohol directly with the metal. Any Grignard reagent is suitable for this 'm'onium chloride solution;

purpose and among the metal alkyls which may be used are phenyllithium, butyllithium, triphenylmethylsodium and other similar reagents.

The reaction between the metal derivative of propargyl alcohol and the 1-acyloxy-3-butanone is preferably carried out in an inert solvent such as diethyl ether, tetrahydrofur'ane and others.- Certain hydrocarbons such as pentane, hexane, benzene, and toluene may be used but are not as good as the preferred solvents mentioned.

The hydrolysis is accomplished by the addition of water. Other materials'such as ammonium chloride or acids such as acetic acid may be added to facilitate the removal of metal salts' formed. during the hydrolysis.

The specific examples illustrated in the drawings disclose the synthesis of G-trim-ethylacetoxy-4-methy1hexyne-2-diol-1,4 and the 6 benzoxyl-methylhexyne 2 diol-1,4. For in stance, there is illustrated the reaction of a solution of i-l'iydroxy-3-butanorieand pyridine with trimethylacetyl chloride; the dissolving of the pyridine hydrochloride with water; extraction of the reaction product with ether; and .vacuum. distillation to yield a 1-trimethylacetoxyB-buta- Iione. Thereafter in synthesizing the trimethylacetoxy methylhexyne=diol from the butanone, the illustrated process consists in general of re= acting phenyllithium and propargyl alcohol in ether; the addition thereto of the l-trimethylacetoxy-3-butanone and the reaction thereof; the hydrolysis of the reaction product by an amextraction of the product with. ether; and the distillation of the 6- trimethylacetoxy-4-methylhexyne2dio1-1,4.

The reactions involvedin this specific example are shown by the following equations:

The other specific process illustrated consists of the reaction. of benzoyl chloride with l-hydroxy-3-butanone in solution in ether and py-- ridine, the pyridine acting first as a. catalyst and later combining to form pyridine hydrochloride with the hydrogen chloride formed by the condensation of the hydroxybutanone with the b'enzoxy chloride; addition of water to dissolve the pyridine hydrochloride; extraction of the condensation product by ether; and vacuum distillation to give 1-b'enzoxy-3-butano'ne; the reaction of .phenylmag'nesium bromide with propargyl alcohol to form a propargyl magnesium bromide; the reaction of this propargyl magnesium complex with the benzoxy-butanone previously formed; hydrolyzation of the. product; neutralization of excess acid; and distillation of the products to isolatea G-benzoizyA-methyk 4 hexyne-2-diol-L4. The reaction equations in this specific example are as follows:

g BHsN (JEFF-01120112011 o1 C5H5 noon ozcn zofiniM -nr final products obtained by these methods are intermediate products useful in the production of vitamin A and vitamin A esters and in the synthetic production of other chemical compounds.

To further characterize the benzoxybutanone of the above process, I reacted thel-benzoXy-3- butanone with hydroxylamine hydrochloride and sodium hydroxide to obtain 1-benzoxy-3-butanone oxime. L (Fig. 8.)

To further characterize the 6-benzoxy-4- methylhexyne-Ldiol-1,4, I reacted it with p-nitrobenzoyl chloride to form a di-p-m'trobenzoate of 6 benzoxy 4 methylhexyne 2. diol 1,4.

4 (Fig. 7.)

The following Examples I to VI, inclusive, are presented in illustration of my invention but the inventions are not to be considered as limited to the specific examples.

EXAMPLE I Preparation of 1-trimethylacetoxy-3-butanone To an ice cold solution of 49 g. (.56 mole) of 5 i'hydroxy3 butanone and 48 g'. (.6 mole) of pyridine, there was added dropwise with stirring V EC alcd. as CnHmOal].

Theoretical I Found O..- 62.8 i 63.0 63.0 H 9.4l 9.8 9.8

Semicarbazonc, M. P. 133-134".

product has the following structural formula;

on CH3 ll cH2cH -oo-o-o:a

reduced pressure.

EXAMPLE 11 Preparation of 6-trimethylaceto:cy-4-methylhexyne-Z-dzoZ-IA To .a. cold solution of 0.5 mole of phenyllithium in 460 cc. of ether there was added 14 g. (.25 mole) of propargyl alcohol in ether. The addition required 45 minutes and stirring was continued for an additional minutes.

To the stirred complex there was added 47.3.g.

(.275 mole) of 1-trimethylacetoxy-3-butanone in. The addition was rapid and the reaction ether. was cooled throughout the process. .1

.After stirring one-half an hour saturated ammonium chloride solution was added and the product was isolated by ether extraction. followed by distillation on a Hickman still under greatly The distillate solidifiedand was recrystallized from petroleum ether B. P. 90- 100" C.) and ether. M. P. 54.4-55.5 C.

[Calcd as CizH2o 4-] I Theoretical Found 63.2 63.2 as as 8.7

' The product has the following structural formula:

0115 l o CH3 Preparation of I-beneozcy-S-butjartone T To 500 cc. of dry ether there was added 71.2%.

(.81 mole) of l-hydroxy-3-butanone and 70g.

(1.0 mole) of pyridine. The reaction vesse l was surrounded by an ice bath and there was added with stirring over the period of one hour 120g. (.85 mole) of benzoyl chloride. Stirring was" continued for three and one-half hours and then the reaction was allowed to stand overnight.

Water was added to dissolve the pyridine hydrochloride and the reaction was stirred two hours to hydrolyze any excess benzoyl chloride;

The product was isolated by ether extraction' and vacuumdistillation. Yie1d-145.0--g:= (95%) of ester; B. P. 106.5-108.5 at

0.5 m. It's'structural formula is: on

%-cHzoH.-0-o-o m 0 EXAMPLE IV I Preparation of 6-benzoary-4-methylhexyne-2:

did-1,4

To 470 ml. (1 mole) of 2.13 mole phenylmagnesium bromide, diluted with an equal volume of benzene, there was added 28 g. (0.5 mole) of propargyl alcohol in 300 ml. of benzene. To the resulting complex there was added 96 g. (.5 mole) of l-benzoxy-3-butanone in 300 ml. of benzene. The reaction was stirred one half an hour and hydrolyzed with dilute acetic acid.

.After neutralization of excess acetic acid with Yield of product;

sodium bicarbonate. the product was isolated by ether extraction.

Vacuum distillation yielded 34.8 g. of material, B.'P; 8341 7 at0.5 mm. which consisted of starting material'and some biphenyl. The residue weighed 74.8 g. The residue was distilled on a Hickman still under greatly reduced pressure yielding the following results:

' Presl Fraction Bath Sure, weight Perfllelnt mm Hg 1e c 156-170 .04 32.3 -Residue .04 16.0

alcohol-water to a constant melting point of 93.5-91.5". a

[Qalcd. as CnHia sJ Theoretical Found The structuralformula of the product is:

- -CHzOH7 -O%CGH5 -EXAMPLE VI Preparation of di-pmtrob enzoate of 6- benzoxy- -4methylhea:yne-Z-dioZ-I,4

To 0.7 g. of 6-benzoxy-4-methy1hexyne-2-diol- .1,4 in 5--10 cc. of pyridine there was added 1.1 g.

of." p-nitrobenzoyl chloride. The whole was heatedto reflux and then poured in water. The amorphoussolid was separamd and crystallized from-:alcohol. .AfllGl several recrystallizations,

the product meltedat 109.0-109 .6 0.

[Galcd as C28H29010N2.]

Theoretical Found The structural formula of the product is Although the com-positions of matter and processes shown and described in illustration of the present inventions in the foregoing specification constitute preferred forms, and I wish it 1 to be understood that I do not desire to be limited to the exact details of the composition of matter and processes shown and described, for obvious modifications will occur to a person skilled in the art, all coming within the scope of the claims which follow.

I claim: 1. As a new article of manufacture a compound of the formula H3 HOCHZ-CEC(IIOEQ-CHE-R wherein R is a member of the group consisting of the acetoxy and benzoxy radicals. 1

2. A new article of manufacture consisting of 6-benzoxy-4-methylhexyne-2ediol-1,4.

3. As a new article of manufacture, a methylhexyne-diol consisting of a compound having the general structural formula of 4. A method of synthesizing a methylhexynediol which comprises the steps of adding a halide, having a formula of RX in which R is a member selected from the group consisting of benzoyl and acetyl radicals and X is a halogen atom, to a solution of 1-hydroxy-3-butanone in the presence of an acid-binding agent; isolating and purifying the resulting butanone; mixing a propargyl metallic complex with the butanone; hydrolyzing the reaction product; and isolating the resulting 6-acyl-4-methylheXyne-2-diol-1,4, where the acyloxy member is selected from the group consisting of benzoxy and acetoxy radicals.

5. A method of synthesizing a vitamin A in-- termediate which comprises the steps of adding an acetyl halide to a solution of 1-hydroXy-3- butanone in the presence of an acid-binding agent; isolating and purifying the resulting 1-- acetoxy3-,butanone; mixing a propargyl metal complex with the acetoxy butanone; and hydrolizing the reaction product.

6. A method of synthesizing a methylhexynediol which comprises the steps of addingtrimethylacetyl chlorideto a solution of l-hydroxy- 3-butanone and pyridine; adding water to dissolve the pyridine hydrochloride formed; extracting the product; distilling under vacuum to produce a 1-trimethylacetoxy-3-butanone; mix- 5 tion; extracting the product with ether; and distilling to isolate a trimethylacetoxy-4-methylhexyne-2-diol-l.,4.

7. A process of forming 6-benzoxy-4-methylhexyne-2-diol-1,4 which comprises the steps of reacting a propargyl metal derivative with lbenzoxy-3-butanone; hydrolyzing the resulting complex; and isolating the desired product.

8. A process of forming 6-benzoxy-4-methylhexyne-2-diol-1,4 which comprises the steps of mixing phenylmagnesium bromide with propargyl alcohol; adding l-benzoxy-3-butanone; hydrolyzing'; extracting the product; and distilling the extracted product.

9. A method of forming a 6-benzoxy-4-methylhexyne-2diol-l,4 which comprises the steps of reacting 1-hydroxy-3-butanone with benzoyl chloride in the presence of an acid-binding agent; and reacting the ester so formed with a propargyl metal derivative.

MELVIN S. NEWMAN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,010,828 Rothrock Aug. '13, 1935 2,253,342 Mikeska et al Aug. 19, 1941 2,369,157 Milas Feb. 13, 1945 2,369,159 Milas Feb. 13, 1945 2,382,085 Milas Aug. 14, 1945 2,382,086 Milas Aug. 14, 1945 2,412,465 Milas Dec. 10, 1946 OTHER REFERENCES Buchman, Jour. Am. Chem. 800., 67, 400-403 (1945). 

1. AS A NEW ARTICLE OF MANUFACTURE A COMPOUND OF THE FORMULA 